Differential Impact of Pharmacokinetic and Pharmacodynamic Variability on Response to Combination Therapy

Interindividual variability (IIV) in drug response complicates both fixed-dose design and individualized therapy. Understanding how pharmacokinetic (PK) and pharmacodynamic (PD) processes jointly shape this variability is essential, particularly in combination therapy, where multiple interacting pathways influence outcomes. This study employed a unified PK-Signal-Reaction-Stimulus-Response (PK-SRSR) modeling framework to quantify and compare the impact of IIV in PK and PD parameters under monotherapy and combination therapy. Monte Carlo simulations were used to generate response distributions across hypothetical physiological conditions, while Sobol variance-based sensitivity analysis decomposed total response variability into contributions from individual parameters (FOI) and their interactions (TOI). Results showed that PD variability, especially that related to system-level modulatory processes (S0A, S0B, βA, βB, and βiA), exerted a greater influence on overall response than drug effect level PD (SmaxA, SmaxB, KA, and KB) variability and PK (CLA/F and CLB/F) variability. Variability in response was most sensitive to S0B, βB (FOI > 34%, TOI > 32%) during monotherapy and SmaxA (FOI > 25%, TOI > 27%), SmaxB (FOI > 17%, TOI > 24%), and βB (FOI > 32%, TOI > 34%) during combination therapy. At 45% CV in all parameters, variability in response was lower during combination therapy (CV = 44%, 42%, and 33%) than during monotherapy (CV = 59%, 52%, and 53%) for additive, antagonistic, and synergistic PD interactions, respectively. Introducing a second drug targeting a modulatory pathway reduced response variability by stabilizing regulatory mechanisms, explaining previous observations in which patients achieve therapeutic response despite suboptimal plasma concentrations during combination therapy. Coordinated dose optimization of all agents, supported by response-guided, system-aware strategies, may yield more robust, consistent, and individualized treatment outcomes than traditional PK-guided dosing approaches.